Apoptosis Chapter 9. Neelu Yadav PhD

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1 Apoptosis Chapter 9 Neelu Yadav PhD 1

2 Apoptosis: Lecture outline Apoptosis a programmed cell death pathway in normal homeostasis Core Apoptosis cascade is conserved Compare and contrast between apoptosis, autophagy and necrosis Mechanism/signal transduction in apoptosis Role of mitochondria Role of caspases Intrinsic and extrinsic pathway Methods of apoptosis study Role in tumorigenesis Other mechanisms of cell death, autophagy, mitophagy 2

3 Why cells decide to die? - Stress, harmful, not needed - Completed its life span Death stimulation or Stress Cell Survival Death 3

4 Functions of PCD during Development Involution of the mammary gland after lactation Fuchs and Steller. Cell Volume 147, Issue

5 Types of Cell Death Cell Death Controlled cell death Uncontrolled cell death Physiological cell death or Programmed cell death Autophagic cell death (Type II) Necrotic cell death (?) (Type III) Apoptotic cell death (Type I) Caspase-independent Caspase-dependent Extrinsic pathway Intrinsic pathway (Death receptor-mediated) 5

6 Types of Cell Death Fink and Cookson, Infect Immun

7 Evolutionary Conservation of the Core Apoptotic Machinery Yaron Fuchs, Hermann Steller Cell Volume 147, Issue

8 What is the difference between key cell death mechanisms Apoptosis -Genetically programmed -Extra and intracellular -Cell shrinkage -Blebbing -Organelle intact -Chromatin condensation -DNA fragmentation (laddering) -Phagocytosis with no inflammation -Caspase-dependent Autophagy Genetically programmed Extra and intracellular Autophagic vacuoles Blebbing Sequesteration Partial condensation No laddering Phagocytosis with no inflammation Caspase-independent Necrosis Not (?) genetically Acute injury (?) (Extra) Cytoplasm swelling Disruption of Memb Disruption Non-condensed No laddering Release of intracellular contents & inflammation Caspase-independent 8

9 What is Apoptosis? - A predominant form of cell death - A sequence of events involving various class of proteins - Genetically programmed and evolutionarily conserved Hallmarks of Apoptosis 9

10 Why should we study apoptosis? Intact death program is required for successful embryonic development and maintenance of normal tissue homeostasis Insufficient or evasion of apoptosis manifests as: - Cancer - Autoimmunity (proliferation of immune system cells that recognize and attack self antigens) - Viral infections (removal of virally infected cells by apoptosis) While accelerated cell death is related to: - Neurodegenerative diseases - Immunodeficiency, i - Infertility - Hematologic diseases 10

11 Major Players in Apoptosis -Bcl-2 family proteins -Antiapoptotic -Proapoptotic multi-domain proteins -Proapoptotic BH3-only domain protein -Caspases -Initiator caspases -Executioner caspases 11

12 Bcl-2 family proteins 12

13 Bcl-2 family proteins Various cell-physiologic stresses operate through different proapoptotic proteins to antagonize antiapoptotic proteins such as Bcl2/Bcl-xL. BH3-only proteins sense signals and galvanize action. 13

14 Bcl-2 family proteins-mediated apoptosis 14

15 BAD: Phosphorylation sequesters it in the cytosol 15

16 Bcl-2 family proteins-mediated apoptosis 16

17 Regulation of Bcl-2 and Bcl-xL: Post-translational modifications *Bcl-2 must change conformation (or be activated ) on the mitochondria to inhibit Bax (Dglugosz PJ, EMBO J. 25, 2287, 2006). *Bcl-2 and Bcl-xL (and other prosurvival members) are the guardians of the mitochondria: they are inactivated when BH3-only proteins juxtapose their BH3 domain to Bcl-2 (protein-protein interaction).. *These proteins are transcribed into multiple splice variants. *Bcl-2 is phosphorylated by many apoptotic stimuli. Phosphorylation of Bcl-2 within the flexible loop generally inhibits its anti-apoptotic activity. But it has also been reported that phosphorylation is required for its apoptosis-inhibitory effect. *Bcl-2 and Bcl-xL can also be cleaved by caspases during apoptosis. Cleaved proteins turns themselves into apoptotic killers. *Bcl-xL may undergo deamidation: deamidation of Asn imparts susceptibility to apoptosis by disrupting the ability of Bcl-xL to block the proapoptotic activity of BH3-only proteins. D. Tang 17

18 Mitochondria 18

19 Mitochondrial respiratory chain 19

20 Mitochondrial Porin or PTP (permeability transition pore) Newmeyer, D.D., and Ferguson-Miller, S. Cell 112, ,

21 OMM permeabilization, PTP, and Mitochondrial fission Newmeyer, D.D., and Ferguson-Miller, S. Cell 112, ,

22 Casp-3/7 may be involved in feedback cyt. c release Lakhani SA et al., Science 311, 847, 2006 Adrain and Martin Science 311, 785,

23 Caspases Types of caspases: -Initiator caspases: caspase-2, -8, -9 and -10 -Executioner Caspases: caspase-3, -6 and -7 Caspase Structure: p3-26 Prodomain p20 p10 Large subunit Small subunit Linker Caspase prodomains: Prodomains:In executioner caspases: ~3kd In initiator caspases: kd D. Chandra 23

24 Caspases 24

25 Caspases: Executioner caspases Initiator caspases Mol. Cell 9, ,

26 26 Ledgerwood and Morison Clin Cancer Res 2009

27 Caspase substrates Proteosome components (Mol Cell 14, 81-93, 2004) Mitochondrial complex I p75 subunit (Cell 117, , 2004) 27

28 IAPs 28

29 IAPs function as critical prosurvival molecules *IAPs (especially XIAP) are generally overexpreessed in multiple types of cancer cells apoptotic stimulatio n Smac (second mitochondrial activator of caspases) Shi, Y. Mol. Cell, 9, ,

30 Mechanisms of Caspase Activation and Inhibition Shi, Y. Mol. Cell, 9, ,

31 Known apoptotic pathways to activate caspases - Intrinsic pathway - Extrinsic pathway or death-receptor pathway - Other alternative pathways - Caspase-independent apoptosis 31

32 Extrinsic Apoptotic pathway (death receptor) 32

33 Crosstalk between two pathways 33

34 How to detect apoptosis? -Cell morphology by using microscopy -Cytochrome c release by immunolabelling and Western -Western Blot for caspases and their substrate -DAPI and Annexin-V-staining -Detection of apoptosome using gel filtration 34

35 Immunolabeling, subcellular fractionation and Western blot Cells homogenized Differential centrifugation Cytosol Mitochondria SDS-PAGE and Western 35

36 Caspase cleavage and DAPI labeling 36

37 Detection of Apoptosome 37

38 What happens to the apoptotic cells? 38

39 What happens to the apoptotic cells? 39

40 Apoptosis and Tumorigenesis 1) Upregulation of Bcl2, BclxL, IAPs, Flip etc. 2) Downregulation/ mutation of Bax, Bak, BH3-only protein, Death-receptors, Apaf-1 etc. 40

41 Apoptosis based strategies for cancer therapy 41

42 Exploiting apoptotic machinery for cancer therapy 42

43 Importance of BH3-only protein mimetics in cancer therapy 43

44 Take Home message from apoptosis: -A predominant form of cell death from worm to mammals -Bcl-2 family proteins make decision to die or live -Caspases are the main soldiers in the battle field to execute apoptosis -Mitochondrion is the center point for all activities -Targeting Bcl-2 family proteins have enormous potential in cancer therapy -Finding N-terminal smac/diablo mimetics will counter IAPs -Applications of death ligands such as TNF-α, TRAIL etc. 44

45 Other apoptosis/survival functions of Bcl2-family proteins and caspases Bcl-2 and Bcl-xL can also be cleaved by caspases during apoptosis and this cleaved fragments function as proapoptotic proteins. These proteins also undergo posttranslational modifications, which can also impact on apoptosis sensitivity. Pro-apoptotic BH3-only proteins such as Bad, Bid, Puma, Noxa have also been shown to possess prosurvival roles Caspase-3 activation is involved in cancer cell invasion Caspase-8 is required by NF-kB activation and promotes cell motility 45

46 Caspase-independent cell death Tait and Green, Oncogene

47 Autophagy First recognized under EM early 1960s. Also called macroautophagy: Self-eating to survive. A unique form of membrane trafficking in which membrane compartments (autophagosomes) engulf both organelles and cytosolic macromolecules and deliver them to the lysosome for degradation. 47

48 Autophagy Yoshimori T et al., Cell 128, , 2007 Qu X et al., Cell 128, ,

49 Autophagy Martin Lotz, et al. Nat Rev Rheumatol

50 Autophagy Sagar B. Kudchodkar, et al. Rev Med Virol

51 Mitophagy Green et al., Science

52 Autophagy and Cancer 52 Gutian Xiao. Cytokine Growth Factor Rev. 2007

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